The serum albumins belong to a multigene family of proteins that includes alpha-fetoprotein and human group-specific component, also known as vitamin-D binding protein. The members of this multigene family are typically comprised of relatively large multi-domain proteins, and the serum albumins are the major soluble proteins of the circulatory system and contribute to many vital physiological processes. Serum albumin generally comprises about 50% of the total blood component by dry weight, and as such is responsible for roughly 80% of the maintenance of colloid osmotic blood pressure and is chiefly responsible for controlling the physiological pH of blood.
The albumins and their related blood proteins also play an extremely important role in the transport, distribution and metabolism of many endogenous and exogenous ligands in the human body, including a variety of chemically diverse molecules including fatty acids, amino acids, steroids, calcium, metals such as copper and zinc, and various pharmaceutical agents. The albumin family of molecules are generally thought to facilitate transfer of many of these ligands across organ-circulatory interfaces such as the liver, intestines, kidneys and the brain, and studies have suggested the existence of an albumin cell surface receptor. See, e.g., Schnitzer et al., P.N.A.S. 85:6773 (1988). The albumins are thus involved in a wide range of circulatory and metabolic functions.
Human serum albumin (HSA) is a protein of about 66,500 kD and is comprised of 585 amino acids including at least 17 disulphide bridges. As with many of the members of the albumin family, human serum albumin plays an extremely important role in human physiology and is located in virtually every human tissue and bodily secretion. Human serum albumin is the major protein of the circulatory system and as such is involved in the attachment, distribution and metabolism of all known pharmaceuticals because of its particular binding affinities to these chemicals. The atomic structure and particular details regarding the binding affinities of albumin and the specific regions primarily responsible for those binding properties have been previously determined as set forth, e.g., in U.S. Ser. No. 08/448,196, filed May 25, 1993, now U.S. Pat. No. 5,780,594 and U.S. Ser. No. 08/984,176, filed Dec. 3, 1997, now U.S. Pat. No. 5,948,609, both of which are incorporated herein by reference. Other articles or references of relevance with regard to human serum albumin include Carter et al., Advances in Protein Chemistry, 45:153-203 (1994); Peters, Jr., “All About Albumin”, Academic Press (1995); Camerman et al., Can J. Chem., 54:1309-1316 (1976); Lau et al., J. Biol. Chem., 249:5878-5884 (1974); Callan et al., Res. Commun. Chem. Pathol. Pharmacol., 5:459-472 (1973); and Nieboer et al., Br. J. Ind. Med., 41:56-63 (1984); and all of these references are incorporated by reference as well.
It is also widely known and understood that the amino acid sequences in the different animals vary from humans in differing degrees, from essentially 98% homology for chimpanzees to a more typical value of approximately 60% for other animals such as dogs, mice, rats, etc. While data has shown the overall conservation of the three-dimensional structure of albumin from other species, the specific residues involved in the ligand binding chemistry are distinctly different and account for sometimes quite different pharmokinetics and toxicity involving drug experiments with animal models. As a result, the literature is replete with examples of drugs which appeared to be extremely effective in animal testing only to show extremely disappointing results when used in human trials.
There is thus a significant need to develop new animal models which can more accurately be utilized in toxicological and pharmokinetic studies so as to more accurately reflect how a particular drug or other chemical will work in humans.